JP2020523132A - Surgical fasteners with broad spectrum MMP inhibitors - Google Patents

Abstract

Methods and devices are provided to promote wound healing. Broadly, surgical staplers and staple components comprise of at least one broad spectrum matrix metalloproteinase (MMP) inhibitor that is effective in preventing MMP-mediated extracellular matrix degeneration during wound healing in tissues. Supplied with an effective amount.

Description

Surgical instruments and methods are provided having broad spectrum MMP inhibitors.

Surgical staplers are used in surgical procedures to close openings of tissues, blood vessels, conduits, shunts, or other objects or body parts associated with a particular procedure. The opening may be naturally occurring, such as a passageway in a blood vessel or internal organs such as the stomach, or by forming a bypass or anastomosis with tissue or vascular puncture, or tissue during a stapling procedure. It may be formed by the surgeon during a surgical procedure, such as by an incision.

Most staplers have a handle with an elongated shaft, which at its end has a pair of movable opposed jaws formed to retain and form staples therebetween. The staples are typically contained in staple cartridges, which may contain multiple rows of staples, within one of the two jaws, for ejection of staples to a surgical site. Often located in. In use, the jaws are positioned such that the objects to be stapled are located between the jaws and the staples are ejected and shaped when the jaws are closed and the device is actuated. Some staplers include a knife configured to move between rows of staples in a staple cartridge and to longitudinally cut and/or open stapled tissue between the stapled rows. There is.

Although surgical staplers have been improved over the years, there are still many problems with themselves. One of the more common problems is that the staples form holes as they penetrate the tissue or other object in which they are placed, so leakage can occur. Blood, air, gastrointestinal fluid, and other fluids may seep through the openings formed by the staples, even after the staples are fully formed.

Accordingly, there remains a need for improved devices and methods for stapling tissues, blood vessels, conduits, shunts, or other objects or body sites so as to minimize leakage at the staple insertion site. ..

Broadly, surgical staplers and components of surgical staplers are provided having at least one releasable broad spectrum matrix metalloproteinase (MMP) inhibitor for delivery to the tissue surrounding the staple site. It

In one aspect, a staple cartridge assembly including a cartridge body is provided for use with a surgical stapler. The cartridge body has a plurality of staple cavities. Each staple cavity has a surgical staple disposed therein. The cartridge body can also include a biocompatible supplemental material releasably retained on the cartridge body and configured to be delivered to tissue by deployment of staples within the cartridge body. The staple cartridge assembly is also effective in preventing MMP-mediated extracellular matrix degeneration during wound healing in tissues in a predetermined manner, in an effective amount of at least one broad spectrum matrix metalloproteinase (MMP) inhibitor. Can have an agent.

In one embodiment, the at least one broad spectrum MMP inhibitor is on at least a portion of the plurality of staples, such as at least one of a first leg, a second leg, and a crown of the plurality of staples. Can be located at. In other aspects, an effective amount of at least one broad spectrum MMP inhibitor may be disposed within and releasable from the adjunct material. A broad spectrum MMP inhibitor can inhibit at least 5 of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP12, MMP13, MMP14, and MMP16. The MMP inhibitor can be an anti-inflammatory agent, such as GM6001 (Ilomasat), or a tetracycline class antibiotic, such as doxycycline or minocycline. The broad spectrum MMP inhibitor is also at least one of Levimasat, Batimastat (BB-94), BB-1101, CGS-27023-A, Marimasat, ONO-4817, Ro28-2653, and SB-3CT. obtain. The MMP inhibitor can inhibit four or less of MMP1, MMP2, MMP3, MMP9, MMP9, MMP12, MMP13, MMP14, and MMP16, and MMI-166, Tanomastat, Cipemasterat, MMI-270, ABT-. 770, purinomasat, tetrahydropyran, RS-130830, and 239796-97-5. The MMP inhibitor can be encapsulated on the plurality of staples or adjunct materials by the absorbable polymer or attached as pendant molecules on the adjunct material.

In another aspect, an end effector for a surgical instrument, in one implementation, has a first jaw having a cartridge body having a plurality of staple cavities configured to seat staples therein and tissue thereof. A second jaw having an anvil having a plurality of staple forming cavities on a surface facing the front. At least one of the first jaw and the second jaw may be movable relative to the other. The end effector also, in some implementations, comprises a biocompatible adjunct material releasably retained on the cartridge body configured to be delivered to tissue by deployment of staples within the cartridge body. You can The end effector provides an effective amount of at least one broad spectrum matrix metalloproteinase (MMP) inhibitor that is effective in preventing MMP-mediated extracellular matrix degeneration during wound healing in tissues in a predetermined manner. It may further be included.

In a further aspect, provided herein is a method for temporarily inhibiting wound healing at a surgical site immediately following surgical stapling of tissue with a surgical stapler. The method includes engaging tissue between the cartridge assembly and the anvil of the end effector and actuating the end effector to eject staples from the cartridge assembly into the tissue. The method can optionally include attaching the supplemental material to an end effector of the surgical stapler and extending staples therethrough to maintain the supplemental material at the surgical site. .. At least one of the plurality of staples and a portion of the supplemental material can include an effective amount of at least one broad spectrum matrix metalloproteinase (MMP) inhibitor, the release of the MMP inhibitor in a predetermined manner. MMP-mediated extracellular matrix degeneration during wound healing in tissues can be prevented.

In one embodiment, the MMP inhibitor for use in any of the devices or methods disclosed herein is MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP12, MMP13, MMP14, and MMP16. Of at least 5 of the following, levimasat, batimastat (BB-94), doxycycline, minocycline, GM6001 (ilomastat) and BB-1101, CGS-27023-A, marimasat, ONO-4817, Ro28-2653, And at least one of SB-3CT. The MMP inhibitor may be released immediately after delivery to the tissue, or release may be delayed for hours or up to 1, 2, or 3 days. In other aspects, the MMP inhibitor can inhibit four or less of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP12, MMP13, MMP14, and MMP16, and MMI-166, Tanomastat, Cipemasterat. , MMI-270, ABT-770, purinomasat, tetrahydropyran, RS-130830, and 239796-97-5. In some aspects, the tissue can be colon tissue, such as colon tissue immediately following surgical resection.

The invention will be more fully understood by reading the following detailed description in conjunction with the accompanying drawings.
FIG. 3 is a perspective view of one embodiment of a surgical stapler. 2 is an enlarged view of the distal portion of the surgical stapler of FIG. 1. FIG. 2 is a perspective view of a firing bar of the surgical stapler of FIG. 1. FIG. The firing bar has an E-beam at its distal end. FIG. 8 is a perspective view of another embodiment of a surgical stapler. FIG. 8 is a perspective view of yet another embodiment of a surgical stapler.

Specific exemplary embodiments are described below to provide a thorough understanding of the principles of structure, function, manufacture, and use of the devices and methods disclosed herein. Examples of one or more of these embodiments are illustrated in the accompanying drawings. Those skilled in the art will appreciate that the apparatus and methods specifically described herein and illustrated in the accompanying drawings are non-limiting exemplary embodiments, and the scope of the invention is It will be understood that it is defined only by the claims. Features illustrated or described in connection with one exemplary embodiment may be combined with features of other embodiments. Such modifications and variations are intended to be included within the scope of the present invention.

Further, in the present disclosure, like-referenced components of the embodiments generally have similar features, and thus, in particular embodiments, each of the similarly-referenced components Features are not necessarily described in full detail. In addition, to the extent that linear or circular dimensions are used in the description of the disclosed systems, devices, and methods, such dimensions determine the types of shapes that can be used in combination with such systems, devices, and methods. It is not meant to be limiting. One of ordinary skill in the art will appreciate that the dimensions corresponding to such linear and circular dimensions for any geometry can be readily determined. The size and shape of the systems and devices and their components are at least the anatomy of interest within which the systems and devices are used, the size and shape of the components with which the systems and devices are used, and the systems and devices. May depend on the method and procedure used.

It will be appreciated that the terms "proximal" and "distal" are used herein with reference to a user, such as a clinician, holding the handle of the instrument. Other spatial terms such as "anterior" and "posterior" likewise correspond to distal and proximal, respectively. It will be further understood that, for convenience and clarity of explanation, spatial terms such as "vertical" and "horizontal" are used herein with respect to the drawings. However, surgical instruments are used in many orientations and positions, and these spatial terms are not intended to be limiting and absolute.

Various exemplary devices and methods are provided for performing surgical procedures. In some embodiments, devices and methods for open surgical procedures are provided, and in other embodiments, devices and methods for laparoscopic, endoscopic, and other minimally invasive surgical procedures. A method is provided. These devices may be fired directly by a human user or remotely under the direct control of a robot or similar operating tool. However, one of ordinary skill in the art will appreciate that the various methods and devices disclosed herein may be used in numerous surgical procedures and applications. The various devices disclosed herein are inserted into the body in some manner, such as through a natural opening, through an incision or puncture formed in tissue, or using an access device such as a trocar cannula. Those skilled in the art will further recognize that this can be done. For example, the working or end effector portion of these instruments may have an access device with a working channel that can be inserted directly into the patient's body or that can pass through the end effector and elongated shaft of a surgical instrument. Can be inserted through.

During surgical procedures, the patient's tissue may be injured (eg, excised, torn, punctured, etc.) in any of a variety of ways. A wound may be an intended aspect of a surgical procedure, eg, during an anastomosis and/or when tissue is cut and fastened using a surgical device, eg, a surgical stapler. Wounded tissue typically heals over time in a generally the same manner for all patients.

Wound healing is traditionally thought to involve four stages: hemostasis, inflammation, proliferation, and remodeling. The hemostasis stage generally involves blood clotting, eg, cessation of bleeding. In general, injured blood vessels reduce blood flow by contracting, helping platelets aggregate and seal the wound site, which activates fibrin to further promote wound sealing. However, blood clots form at the wound site. The inflammatory stage generally involves cleaning the wound site. In general, the immune system provides a response to potential fear of infection at the wound site via signaling to protective immune cells such as neutrophils and macrophages. The proliferative phase generally involves remodeling tissue by tissue growth and angiogenesis (vascular growth). In general, fibroblasts arrive at the wound site, colonize collagen and release growth factors that attract epithelial cells, which in turn attract endothelial cells. The remodeling stage (also called the maturation stage) generally involves augmenting scar tissue at the wound site. Generally, collagen fibers align, crosslink, and mature scars until they eventually disappear.

Each of the four stages of wound healing involves different aspects of the healing process, but the stages typically overlap one another. That is, each of the last three steps typically overlaps with the preceding steps, eg, inflammation overlaps hemostasis, proliferation overlaps inflammation, and remodeling overlaps proliferation. The rate at which the transitions between stages occur generally affects the rate of overall wound healing and thus generally affects patient recovery time, risk of complications, and/or patient comfort. Exert. Similarly, the length of each of the four individual stages generally affects the rate of overall wound healing and the general recovery of the patient.

Matrix metalloproteinases (MMPs) are a group of proteases that degrade components of the extracellular matrix (ECM) of tissues under a variety of physiological and pathological conditions, including during wound healing. These enzymes help remove necrotic and dead tissue, rebuild connective tissue underlying the ECM, promote migration of inflammatory cells to the wound site, and support angiogenesis. During the inflammatory phase of wound healing, MMPs destroy damaged ECM located at the wound edges. This allows new ECM molecules (such as collagen, elastin, and fibronectin) synthesized by cells located at or attracted to the wound site during the later stages of wound healing to be ultimately It fuses with and becomes part of the complete ECM, resulting in wound closure and healing.

Immediately after tissue stapling, cells present at the site of staple insertion release MMPs, which at and near the wound caused by staple insertion to promote the early stages of wound healing. In particular, it initiates the process of degrading the collagen component of the ECM). However, without wishing to be bound by theory, this natural process results in weakening of the tissue surrounding the staple site, at least initially (ie, up to about 3 days after staple insertion), thereby causing laceration and tearing of the tissue. Other complications, such as leakage of blood, air, and other fluids through the openings formed by the staples, and anastomotic leaks, eg, after bowel resection, are likely to occur. Therefore, without wishing to be bound by theory again, immediately after staple insertion, delivery of a substance capable of inhibiting MMP to a wound site (for example, intestinal tissue) in a tissue allows wound healing to be performed. It is believed that the degeneration of the ECM associated with early stages can be prevented or minimized, thereby strengthening the staple insertion site and reducing the likelihood of leakage or rupture.

Previous studies have suggested that multiple MMPs are responsible for ECM degradation immediately following tissue stapling (eg, Stumpf et al., 2005, Surgery 137:229-234 and Pastern et al., 2010). , Coloristic Dis 12:e93-e98). Thus, it may be desirable to use one or more broad spectrum MMP inhibitors with surgical instruments such as surgical staplers to help improve surgical procedures. MMP inhibitors are molecules that can inhibit or reduce the proteolytic activity of MMPs on ECM components at the wound site. Without wishing to be bound by theory, by preventing native MMP-mediated ECM degradation that occurs shortly after staple insertion, a broad spectrum MMP inhibitor enhances the tissue surrounding the wound site, thereby enhancing tissue stapling. It may be possible to prevent complications associated with tissue leakage. In some cases, a broad spectrum MMP inhibitor delivered to the site of tissue stapling, provided by a device according to the methods provided herein, may increase the incidence of scar tissue formation and, after stapling, It leads to the minimization of migration of tissue within and around the staple puncture site that can result from the resulting tissue deformation (eg, lung inflation, gastrointestinal dilation, etc.). One of ordinary skill in the art will recognize that the staple puncture site can be a stress concentrator, and the size of the hole formed by the staple increases as the tissue in its vicinity is placed under tension. Therefore, limiting MMP-mediated degradation of ECM (eg, MMP-mediated proteolysis of collagen) and thus limiting the migration of tissue around these puncture sites promotes scar tissue formation. The size of the holes that can grow under tension as well as the possibility of leakage can be minimized.

Further clinical studies on the use of MMP inhibitors in MMPs and wound healing can be found in Argen et al. , Surgery, 2006, 140(1):72(-82), Klarup, et al. , Int J Colorful Dis, 2013, 28: 1151-1159, Bosmans et al. , BMC Gastroenterology (2015) 15:180, Holte et al. Brit. J. Surg. , 2009, 96:650-54, Siemonsma et al. , Surgery, 2002, 133(3):268-276, Klein et al, Eur. Surg. Res. , 2011, 46:26-31, Moran et al. , World J.; Emergy Surgery, 2007, 2:13, Kaemmer et al. , J. Surg. Res. , 2010, I63, e67-e72, Martens et al. , Gut, 1991, 32, 1482-87, Fatouros et al. , 1999, Eur. J. Surg. , 165(10):986-92, Savage et al. , 1997, 40(8):962-70, Oines et al. , World J Gastroenterol, 2014 20(35): 12637-48, Kiyama et al. , Wound Repair and Regen. , 10(5):308-13, Raptis et al. , Int. J. Coloristic Dis. , 2011, de Hingh et al. , Int. J. Colorectal. Dis. , 2002, 17:348-54, and Hayden et al. , 2011, J. Surgical Res. , 168:315-324, the disclosures of each of which is incorporated herein by reference in its entirety.

Surgical Stapling Instrument A variety of surgical instruments can be used with the agent(s) disclosed herein. Surgical instruments may include surgical staplers. Various surgical staplers may be used, for example linear surgical staplers and circular staplers. Generally, the linear stapler can be configured to form longitudinal staple lines and can include an elongated jaw to which a cartridge containing the longitudinal staple rows is coupled. The elongated jaws can include knives or other cutting members that can form cuts between the rows of staples along the tissue retained within the jaws. In general, the annular stapler may be configured to form an annular staple line and may include an annular jaw having a cartridge containing an array of annular staples. The annular jaw can include a knife or other cutting member that can form a cut inside the row of staples to define an opening through the tissue retained within the jaw. The stapler may be used in a variety of different surgical procedures, such as in chest or gastric surgery, for a variety of different surgical procedures on different tissues.

FIG. 1 illustrates an example of a linear surgical stapler 10 suitable for use with one or more adjuncts and/or agents. The stapler 10 generally includes a handle assembly 12, a shaft 14 that extends distally from a distal end 12d of the handle assembly 12, and an end effector 30 at a distal end 14d of the shaft 14. The end effector 30 has opposed lower jaws 32 and upper jaws 34, although other types of end effectors may be used with the shaft 14, handle assembly 12, and associated components. The lower jaw 32 has a staple channel 56 configured to support the staple cartridge 40. The upper jaw 34 faces the lower jaw 32 and is configured to act as an anvil to assist in deploying the staples of the staple cartridge 40 (the staples are hidden in FIGS. 1 and 2). It has an anvil surface 33 which is formed. At least one of the opposing lower jaw 32 and upper jaw 34 is relative to the other lower jaw 32 and upper jaw 34 to clamp tissue and/or other objects disposed therebetween. Can be moved. In some implementations, one of the opposing lower jaw 32 and upper jaw 34 may be fixed or otherwise immovable. In some implementations, both the opposing lower jaw 32 and upper jaw 34 may be movable. The components of the firing system may be configured to pass through at least a portion of the end effector 30 to eject staples into the clamped tissue. In various implementations, knife blade 36 or other cutting member may be associated with the firing system to dissect tissue during the stapling procedure.

Operation of the end effector 30 may be initiated by input at the handle assembly 12 from a user, such as a clinician, surgeon, or the like. The handle assembly 12 may have many different configurations designed to manipulate and actuate the end effector 30 coupled thereto. In the illustrated embodiment, the handle assembly 12 includes a pistol grip type housing 18 having various mechanical and/or electrical components for manipulating various features of the instrument 10 disposed therein. Have For example, the handle assembly 12 is mounted adjacent its distal end 12d, which may facilitate rotation of the shaft 14 and/or the end effector 30 about the longitudinal axis L of the shaft 14 relative to the handle assembly 12. A rotary knob 26 may be included. The handle assembly 12 may further include a clamp component as part of a clamp system actuated by a clamp trigger 22 and a firing component as part of a firing system actuated by a firing trigger 24. The clamp trigger 22 and firing trigger 24 may be biased to the open position relative to the stationary handle 20, for example by a torsion spring. Movement of the clamp trigger 22 toward the stationary handle 20 can actuate the clamp system described below, which causes the jaws 32, 34 to tip towards each other, thereby clamping the tissue therebetween. can do. Movement of the firing trigger 24 can actuate the firing system described below, which can cause staples to be ejected from the internally disposed staple cartridge 40 and/or advance the knife blade 36. The tissue captured between the jaws 32, 34 can be cut. Those skilled in the art will recognize that various configurations of mechanical, hydraulic, pneumatic, electromechanical, robotic, or other firing system components may be used for staple ejection and/or tissue dissection. Let's do it.

As shown in FIG. 2, the illustrated implementation of end effector 30 has a lower jaw 32 that functions as a cartridge assembly or carrier and an opposing upper jaw 34 that functions as an anvil. A staple cartridge 40 having a plurality of staples therein is supported within a staple tray 37, which in turn is supported within a cartridge channel in the lower jaw 32. The upper jaw 34 has a plurality of staple forming pockets (not shown), each of which is positioned over a corresponding staple from the plurality of staples contained within the staple cartridge 40. The upper jaw 34 may be connected to the lower jaw 32 in a variety of ways, but in the implementation shown, the upper jaw 34 is immediately distal to its engagement with the shaft 14 and near the staple channel 56. It has a proximal pivot end 34p that is pivotally received within the distal end 56p. When the upper jaw 34 pivots downwardly, the upper jaw 34 moves the anvil surface 33 and the staple forming pocket formed on the anvil surface 33 moves toward the opposing staple cartridge 40.

Various clamping components can be used to provide opening and closing of the jaws 32, 34 to selectively clamp tissue therebetween. As shown, the pivot end 34p of the upper jaw 34 includes a closure mechanism 34c distal to its pivotal attachment to the staple channel 56. Thus, the closure tube 46, which includes at its distal end a horseshoe-shaped opening 46a that engages the closure mechanism 34c, is responsive to the clamp trigger 22 to the upper jaw 34 during proximal longitudinal movement of the closure tube 46. An opening movement is selectively provided, and a closing movement is provided to the upper jaw 34 during the distal longitudinal movement of the closure tube 46. As noted above, in various implementations, opening and closing the end effector 30 may be accomplished by relative movement of the lower jaw 32 relative to the upper jaw 34, relative movement of the upper jaw 34 relative to the lower jaw 32, or both jaws relative to each other. It may be brought about by the movement of the parts 32, 34.

The launch component of the illustrated implementation includes a launch bar 35 having an E-beam 38 at the distal end, as shown in FIG. The firing bar 35 is contained within the shaft 14, for example, within the longitudinal firing bar slot 14s of the shaft 14 and is guided by the firing motion from the handle 12. Actuation of firing trigger 24 may affect the distal movement of E-beam 38 through at least a portion of end effector 30, thereby firing the staples contained within staple cartridge 40. As shown, the guide 39 projecting from the distal end of the E-beam 38 may engage the wedge sled 47 shown in FIG. The wedge sled 47 may then push the staple driver 48 up through the staple cavity 41 formed in the staple cartridge 40. The upward movement of the staple driver 48 exerts an upward force on each of the plurality of staples in the cartridge 40, thereby pushing the staples upward against the anvil surface 33 of the upper jaw 34, creating a formed staple. ..

In addition to firing the staples, the E-beam 38 closes the jaws 32, 34, pulls the upper jaw 34 away from the staple cartridge 40, and/or removes tissue trapped between the jaws 32, 34. It can be configured to facilitate cutting. Specifically, the pair of top pins and the pair of bottom pins engage one or both of upper jaw 32 and lower jaw 34 to cause firing bar 35 to advance through end effector 30. The jaws 32, 34 may be squeezed towards each other. At the same time, a knife 36 extending between the top and bottom pins can be configured to cut the tissue captured between the jaws 32, 34.

During use, surgical stapler 10 may be placed in a cannula or port and placed at the surgical site. The tissue to be dissected and stapled may be placed between the jaws 32, 34 of the surgical stapler 10. The mechanism of the stapler 10 can be manipulated as desired by the user and implemented as the desired location for the jaws 32, 34 at the surgical site and tissue associated with the jaws 32, 34. After achieving proper positioning, the clamp trigger 22 may be pulled toward the stationary handle 20 to activate the clamp system. The trigger 22 causes the closure tube 46 to pass distally through at least a portion of the shaft 14 and tip at least one of the jaws 32, 34 toward the other to remove tissue disposed therebetween. The components of the clamping system can be actuated to clamp. Thereafter, firing bar 35 and/or E-beam 38 travels distally through at least a portion of end effector 30, resulting in firing of staples, optionally captured between jaws 32, 34. The trigger 24 may be pulled toward the stationary handle 20 to actuate the components of the firing system to sever cut tissue.

Another example of a surgical instrument in the form of a linear surgical stapler 50 is shown in FIG. The stapler 50 may be generally constructed and used similar to the stapler 10 of FIG. Similar to the surgical instrument 10 of FIG. 1, the surgical instrument 50 includes a handle assembly 52 that includes a shaft 54 that extends distally from the handle assembly 52 and is distal for treating tissue. It has an end effector 60 at the end. The upper jaw 64 and the lower jaw 62 of the end effector 60 capture tissue between, stapling the tissue by firing staples from a cartridge 66 located within the lower jaw 62, and/or Alternatively, it may be configured to make an incision in the tissue. In this implementation, the attachment 67 at the proximal end of the shaft 54 can be configured to allow the shaft 54 and the end effector 60 to be removably attachable to the handle assembly 52. Specifically, the fitting mechanism 68 of the mounting portion 67 can be fitted to the auxiliary fitting mechanism 71 of the handle assembly 52. The mating features 68, 71 may be configured to couple to each other via, for example, a snap fit bond, a bayonet style bond, etc., although any number of auxiliary mating features and any type of bond may be used to secure the shaft 54. It can be used to removably couple to the handle assembly 52. Although the entire shaft 54 in the illustrated implementation is separably configured from the handle assembly 52, in some implementations the attachment 67 allows only the distal portion of the shaft 54 to be removed. Can be configured. The separable coupling of shaft 54 and/or end effector 60 allows for selective attachment of desired end effector 60 for a particular procedure and/or reuse of handle assembly 52 for a number of different procedures. Can be possible.

The handle assembly 52 may have one or more features thereon for manipulating and actuating the end effector 60. As a non-limiting example, a rotation knob 72 attached to the distal end of handle assembly 52 may facilitate rotation of shaft 54 and/or end effector 60 with respect to handle assembly 52. The handle assembly 52 may include a clamp component as part of a clamp system actuated by a movable trigger 74 and a firing component as part of a firing system that may also be actuated by the trigger 74. Thus, in some implementations, movement of the trigger 74 through the first range of motion toward the stationary handle 70 actuates the clamp components to direct the opposing jaws 62, 64 toward each other in a closed position. You can get closer. In some implementations, only one of the opposing jaws 62, 24 may move toward the jaws 62, 64 in the closed position. Further movement of the trigger 74 through the second range of motion toward the stationary handle 70 can activate the firing component to eject staples from the staple cartridge 66 and/or a knife or other cutting. A member (not shown) can be advanced to cut the tissue captured between the jaws 62,64.

An example of a surgical instrument in the form of an annular surgical stapler 80 is illustrated in FIG. The stapler 80 may be generally configured and used in the same manner as the linear staplers 10, 50 of FIGS. 1 and 4, but some mechanism accommodates its function as a ring stapler. Similar to the surgical instruments 10, 50, the surgical instrument 80 includes a handle assembly 82 that includes a shaft 84 that extends distally from the surgical instrument 80 and is an end effector for treating tissue. 90 at its distal end. The end effector 90 may include a cartridge assembly 92 and an anvil 94 each having a tissue-contacting surface having a generally circular shape. Cartridge assembly 92 and anvil 94 may be coupled via a shaft 98 extending from anvil 94 of stapler 80 to handle assembly 82, and actuation of actuator 85 on handle assembly 82 retracts and advances shaft 98. The anvil 94 can be moved with respect to the cartridge assembly 92. The anvil 94 and the cartridge assembly 92 can perform various functions, such as capturing tissue between them, stapling tissue by firing staples from the cartridge 96 of the cartridge assembly 92, and/or , Can be configured to make an incision in tissue. In general, the cartridge assembly 92 can accommodate a cartridge containing staples and the staples can be deployed relative to the anvil 94 to form a circular staple pattern, for example, the outer circumference of a tubular body organ. You can staple around.

In one implementation, the shaft 98 comprises first and second portions (not shown) configured to be releasably coupled to each other so that the anvil 94 can be separated from the cartridge assembly 92. This allows for greater flexibility in placing the anvil 94 and cartridge assembly 92 within the patient's body. For example, the first portion of the shaft may be disposed inside the cartridge assembly 92 and extend distally outside the cartridge assembly 92, terminating in a distal mating feature. The second portion of shaft 84 may be disposed inside anvil 94 and extend proximally out of cartridge assembly 92, terminating in a proximal mating feature. In use, the anvil 94 and the cartridge assembly 92 can be moved relative to each other by coupling the proximal and distal mating features together.

The handle assembly 82 of the stapler 80 can be provided with various actuators that can control the operation of the stapler. For example, the handle assembly 82 may be provided with a rotation knob 86 that facilitates positioning of the end effector 90 by rotation and/or a trigger 85 for actuating the end effector 90. Movement of the trigger 85 toward the stationary handle 87 through the first range of motion can be actuated to move the components of the clamping system closer to the jaw (ie, moving the anvil 94 toward the cartridge assembly 92). Movement of the trigger 85 toward the stationary handle 87 through the second range of motion actuates components of the firing system to deploy staples from the staple cartridge assembly 92 and/or between the cartridge assembly 92 and the anvil 94. A knife may be advanced to cut tissue captured in between.

The illustrated examples of surgical stapling instruments 10, 50, and 80 provide examples of only a few of the many different configurations and associated uses, which are provided herein. Can be used with the disclosure. The illustrated embodiments are all configured for use in minimally invasive procedures, but instruments configured for use in open surgical procedures, eg, US Pat. No. 8,317,070 (of the invention). It is understood that the open linear stapler described in the name "Surgical Stapling Devices That Produce Formed Staples Having Different Lengths", filed February 28, 2007) can be used with the disclosure provided herein. Will. Further details of the illustrated embodiment, as well as further embodiments of the surgical stapler, its components, and their associated methods of use, can be found in U.S. Patent Application Publication No. 2013/0256377 (Title of Invention: "Layer Comprising Deployable Attachment"). "Members," filed February 8, 2013), US Pat. No. 8,393,514 ("Selectively Orientable Immutable Fastener Cartridge", filed September 30, 2010), US Patent No. 8 , 317,070 (Title of Invention: Surgical Stapleting Devices That Produce Formed Staples Having Different Lengths), filed February 28, 2007, US Patent No. 7,143,925 urgical (Inc. EAP Blocking Lockout Mechanism", filed June 21, 2005), U.S. Patent Application Publication No. 2015/0134077 (Invention title "Sealing Materials For Use In Surgical Stapling", filed November 8, 2013). The title of the invention "Sealing Materials For Use In Surgical Procedures", filed on November 8, 2013, U.S. Pat. App. (Filed on Nov. 8), U.S. Patent Application Publication No. 2015/0133996 (named "Positively Charged Implantable Materials and Methods of Forming the Same", filed Nov. 8, 2013) No. 2015/0129634 (Title of Invention Materials and Methods of Using the Same, 2013) Filed on Nov. 8, 2013), U.S. Patent Application Publication No. 2015/0133995 (Hybrid Adjunct Materials for Use in Surgical Stapling, filed on Nov. 8, 2013), U.S. Patent Application No. 14 /226,142 (Title of Invention: "Surgical Instrument Comprising a Sensor System", filed March 26, 2014), and U.S. Patent Application No. 14/300,954 (Title of Invention: "Adjunct Materials and Methods"). Using Same in Surgical Methods for Tissue Sealing", filed June 10, 2014). These documents are incorporated herein by reference in their entirety.

MMP Inhibitors MMPs comprise a family of over 20 members, which use Zn ²⁺ in their active site to catalyze the hydrolysis of ECM components such as collagen. Based on the substrate specificity of MMPs, MMPs can be broadly divided into three subfamilies, collagenase, stromelysin, and gelatinase. MMP family proteins are found in normal physiological processes such as embryonic development, reproduction, angiogenesis, bone development, wound healing, cell migration, learning and memory, and pathological processes such as arthritis, intracerebral hemorrhage and metastasis. Involved in the destruction of the outer matrix. Most MMPs are secreted as inactive proproteins, which are activated when cleaved by extracellular proteinases. The enzyme encoded by this gene degrades type IV and type V collagen, as well as other extracellular matrix proteins.

Under normal physiological conditions, MMPs function in wound healing and remodeling. However, when these enzymes are over-activated, they can over-degrade the ECM, leading to disease states. For example, MMP-2 and MMP-9, both of which are gelatinases, are thought to be involved in the pathogenesis of inflammatory, infectious, and neoplastic diseases in many organs. Overactivity of MMP-8, also known as collagenase-2 or neutrophil collagenase, is associated with diseases such as emphysema and osteoarthritis. Balbin et al. , "Collagenase 2 (MMP-8) expression in Murine Tissue-Remodeling Processes, analysis of its Potential Role in Postpartum Injury of the Uterus." Biol. Chem. , 273(37):23959-23968 (1998). Excessive activity of MMP-12, also known as macrophage elastase or metalloprotease, plays an important role in tumor invasion, arthritis, atherosclerosis, Alport syndrome, and chronic obstructive pulmonary disease (COPD). Fulfill. MMP-1 and MMP-13 are involved in proteolysis of collagen. Excessive degradation of collagen is associated with the development of various diseases including osteoarthritis. For example, P. G. Mitchell et al. , "Cloning, expression, and type II collagenionic activity of matrix metalloproteinase-13 from human human osteoartritic cartridge," J Clin 96 Felt. 1, 97(3):761-768.

As used herein, "matrix metalloproteinase inhibitor" or "MMP inhibitor" refers to at least one matrix metalloproteinase enzyme that naturally occurs in mammals, such as MMPs naturally expressed during wound healing. Inhibits the proteolytic activity of at least 5% (5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% of the proteolytic activity , 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, etc.). Many MMP inhibitors are known in the art. For example, existing MMP inhibitors can be based on hydroxamic acid derivatives, sufronyl amino acids, and sulfonylamino hydrochloride derivatives. The hydroxamic acid moiety in these inhibitors binds to the MMP active site Zn ²⁺ and inhibits enzymatic activity. Furthermore, many peptides are known matrix metalloproteinase inhibitors.

Non-limiting specific examples of matrix metalloproteinase inhibitors that inhibit or reduce the proteolytic activity of MMPs include, but are not limited to, exogenous MMP inhibitors, batimastat (BB-94), ilomasterat (GM6001), Marimastat (BB2516), thiol, doxycycline, squaric acid, BB-1101, CGS-27023-A (MMI270B), COL-3 (metastat, CMT-3), AZD3342, hydroxyurea, hydrazine, endogenous, carbamoylphosphate, Beta-lactam, tetracycline and analogs and homologues of tetracycline, minocycline, 3-(4-phenoxyphenylsulfonyl)propylthiirane, pyrimidine-2,4-dione, BAY12-9566, purinomasat (AG-3340), N-. {1S-[4-(4-chlorophenyl)piperazine-1-sulfonylmethyl]-2-methylpropyl}-N-hydroxyformamide, RO31-9790, 3-(4-phenoxyphenylsulfonyl D propylthiirane, 1,6- Bis[N'-(p-chlorophenyl)-N5-biguanide]hexane, trocade, sodium 1-(12-hydroxy)octadecanyl sulfate, minocycline (7-dimethylamino-6-dimethyl-6-deoxytetracycline), tetrapeptidylhydroxamic acid , N-[(2R)-2-(carboxymethyl)-4-methylpentanoyl]-L-tryptophan-(S)-methyl-benzylamide, N-[(2R)-2-(hydroxyamidocarbonylmethyl) -4-Methylpentanoyl]-L-tryptophan methylamide, N-hydroxy-1,3-di-(4-methoxybenzenesulfonyl)-5,5-dimethyl-[1,3]-piperazine-2-carboxamide, N-{1S-[4-(4-chlorophenyl)piperazine-1-sulfonylmethyl]-2-methylpropyl}-N-hydroxyformamide, triaryl-oxy-aryloxy-pyrimidine-2,4,6trione, 4r Biaryl butyric acid, 5-biaryl pentanoic acid, fenbufen, peptide MMPI, hydroxamic acid, tricyclic butyric acid, biphenyl butyric acid, heterocyclic substituted phenyl v butyric acid, sulfonamide, succinamide, FN-439 (P-aminobenzoyl-Gly- Pro-D-Leu-D-Ala-NHOH, MMP-In h-1), sulfonated amino acids, MMP9 inhibitor I (CTK8G1150), ONO-4817, Ro 28-2653, SB-3CT, neutralizing anti-MMP antibody, and tacrolimus (FK506).

A "broad spectrum MMP inhibitor" inhibits the proteolytic activity of two or more MMPs (such as 2, 3, 4, 5, 6, 7, 8, 9 or more MMPs) by at least 5% (protein. 5% of decomposition activity, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% , 85%, 90%, 95%, or 100% inhibition, etc.). Broad spectrum MMP inhibitors have been primarily developed for the treatment of cancer due to the known role of MMPs in promoting cancer progression. While preclinical studies using these inhibitors have shown strong potential as anti-cancer agents, most clinical studies have not shown efficacy as anti-cancer agents (eg Vandenbroucke et al. , 2014, Nature Rev. Drug. Disc., 13:904-27). In some embodiments, the broad spectrum MMP inhibitor inhibits at least one of MMP8, MMP9, and/or MMP13.

In some implementations, the broad spectrum MMP inhibitor for use in the methods and devices disclosed herein comprises at least 5 MMPs (5, 6, 7, 8, 9, 10, 11, 12, Any of 13, 14, 15 or more MMPs, or 5 or more of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP12, MMP13, MMP14, and MMP16). One example of a broad spectrum MMP inhibitor suitable for use in the surgical stapler devices disclosed herein is batimastat (BB-94), represented by the structural formula:

Batimastat was originally developed as an anticancer drug belonging to a group of drugs called angiogenesis inhibitors. Batimastat has MMP8 and 1 nM _{IC 50} of, an _{IC 50} of MMP7,10nM with an _{IC 50} of MMP3,6nM with an _{IC 50} of MMP2,20nM with an _{IC 50} of MMP1,4nM with an _{IC 50} of 3nM It can inhibit MMP9.

Another example of a broad spectrum MMP inhibitor for use in the methods and devices disclosed herein is BB-1101, represented by the structural formula:

BB-1101 has an _{IC 50} of MMP8,3nM with an _{IC 50} of MMP7,3nM with an _{IC 50} of MMP3,60nM with an _{IC 50} of MMP2,30nM with an _{IC 50} of MMP1,4nM with an _{IC 50} of 8nM Having MMP9, having an IC ₅₀ of ₅ nM, MMP12 having an IC ₅₀ of 7 nM, and MMP14 having an IC ₅₀ of 10 nM.

CGS-27023-A (MMI270B) is a further non-limiting example of a suitable broad spectrum MMP inhibitor for use in the methods and devices disclosed herein and is represented by the following structural formula: It

CGS-27023-A is, MMP9 an _{IC 50} of MMP8,8nM with an _{IC 50} of MMP3,8nM with an _{IC 50} of MMP2,43nM with an _{IC 50} of MMP1,20nM with an _{IC 50} of 33 nM, and 6nM of It can inhibit MMP13 with an IC ₅₀ .

A further example of a broad spectrum MMP inhibitor for use in the methods and devices disclosed herein is doxycycline, represented by the structural formula:

Tetracycline antibiotics such as doxycycline have the ability to inhibit endogenous MMPs. Additionally, the tetracycline analog doxycycline hyclate has been shown for periodontal disease and is the only collagenase inhibitor approved by the US Food and Drug Administration for any human disease (Sorsa, et. al., Ann. Med. 38, 306-321 (2006)). Recent findings suggest a role for bacteria in the wound healing process, especially in intestinal tissue after surgical resection (Boasmans et al., BMC Gastroenterology, 2015, 15:180). For example, it has been shown that viral bacteria with high collagenase activity can contribute to staple destruction. As such, antibiotics such as doxycycline can function not only to inhibit multiple MMPs, but also to kill collagenase-secreting bacteria that can be attracted to the wound site. MMP8 doxycycline has an _{IC 50} of MMP7,26-50μM with an _{IC 50} of MMP3,28μM with an _{IC 50} of MMP2,32μM with an _{IC 50} of MMP1,56μM with an _{IC 50} of> 400 [mu] M, and 2-50μM Can inhibit MMP13 with an IC ₅₀ of

Another non-limiting example of a broad spectrum MMP inhibitor for use in the methods and devices disclosed herein is GM6001 (ilomastat), represented by the structural formula:

GM6001 is a member of the hydroxamic acid class of reversible metallopeptidase inhibitors. The anionic state of the hydroxamic acid group in this molecule forms a bidentate complex with the active site zinc in MMPs, leading to inhibition of MMP function. GM6001 has an _{IC 50} of MMP8,0.2nM with an _{IC 50} of MMP3,0.1nM with an _{IC 50} of MMP2,27nM with an _{IC 50} of MMP1,0.4nM with an _{IC 50} of 0.4 nM MMP9 , And can inhibit MMP14 with an IC ₅₀ of 5.2 nM.

A further example of a broad spectrum MMP inhibitor for use in the methods and devices disclosed herein is marimastat (BB-2516), represented by the structural formula:

Marimastat was an antitumor drug developed and proposed by British Biotech, but it performed poorly in clinical trials for treating cancer. Marimastat has an _{IC 50} of MMP8,3nM with an _{IC 50} of MMP7,2nM with an _{IC 50} of MMP3,20nM with an _{IC 50} of MMP2,200nM with an _{IC 50} of MMP1,6nM with an _{IC 50} of 5nM It is capable of inhibiting MMP9, and MMP14 with an IC ₅₀ of 1.8 nM.

Minocycline is a further non-limiting example of a broad spectrum MMP inhibitor suitable for use in the methods and devices disclosed herein and is represented by the following structural formula:

Minocycline can inhibit MMP9 with an _{IC 50} of MMP7,180μM with an _{IC 50} of MMP3,125μM with an _{IC 50} of 290μM. Minocycline has also been shown to be effective in inhibiting MMP1 and MMP2.

Another example of a broad spectrum MMP inhibitor for use in the methods and devices disclosed herein is ONO-4817, represented by the structural formula:

ONO-4817 has MMP1 with an IC ₅₀ of 1.6 nM, MMP2 with a K _i of 0.73 nM, MMP3 with a K _i of 42 nM, MMP7 with a K _i of 2.5 nM, K _i of 1.1 nM. With MMP8, an MMP9 with an IC ₅₀ of 2.1 nM, an MMP12 with a K _i of 0.45 nM, and an MMP13 with a K _i of 1.1 nM.

Yet another example of a broad spectrum MMP inhibitor for use in the methods and devices disclosed herein is Ro28-2653, represented by the structural formula:

Ro28-2653 is a MMP16 with MMP14 and 91 nM _{IC 50} of, an _{IC 50} of MMP9,96nM with an _{IC 50} of MMP8,12-23nM with an _{IC 50} of MMP2,15nM with an _{IC 50} of 7-246nM Can be inhibited.

SB-3CT is another non-limiting example of a broad spectrum MMP inhibitor suitable for use in the methods and devices disclosed herein and is represented by the following structural formula:

SB-3CT has, MMP8 has a _{K i} of MMP7,1.1nM having a _{K i} of MMP3,96μM having a _{K i} of MMP2,15nM having a _{K i} of MMP1,14nM having a _{K i} of 206MyuM, and 600nM of It can inhibit MMP9 with an IC ₅₀ .

Levimasat (Bms-275291) is a further non-limiting example of a broad spectrum MMP inhibitor suitable for use in the methods and devices disclosed herein and is represented by the following structural formula:

Levimasat is a broad spectrum MMP inhibitor with a thiol zinc bond group. Levimastat has oral bioavailability and is a collagen non-peptidomimetic. Levimasat has some selectivity as it does not inhibit all MMP action. Metalloproteinases that release TNF-alpha, TNF-II, L-selectin, IL-1-RII and IL-6 are not inhibited by, for example, levimasat. Levimasat can inhibit MMP1, MMP2, MMP8, MMP9, and MMP14.

Another example of a broad spectrum MMP inhibitor for use in the methods and devices disclosed herein is MMP9 inhibitor I (CTK8G1150), represented by the structural formula:

In other implementations, no more than 5 broad-spectrum MMP inhibitors for use in the methods and devices disclosed herein (such as any of 5, 4, 3, or 2 MMPs, or MMP1, MMP2, 5 or less of MMP3, MMP7, MMP8, MMP9, MMP12, MMP13, MMP14, and MMP16). In some embodiments, the broad spectrum MMP inhibitor inhibits at least MMP9. These more limited broad spectrum MMP inhibitors can be selected based on the particular MMP expressed in the stapled tissue (eg, inhibition of at least one of MMP8, MMP9, or MMP13). One example of this more limited broad spectrum MMP inhibitor suitable for use in the surgical stapler devices disclosed herein is COL-3 (metastat, CMT-3), represented by the structural formula: It

COL-3 can inhibit the MMP13 having MMP8 and 0.3 [mu] g / ml of _{IC 50,} an _{IC 50} of MMP1,48μg / ml with an _{IC 50} of 34 [mu] g / ml.

Another example of a more limited broad spectrum MMP inhibitor is FN-439, represented by the structural formula:

FN-439 can inhibit MMP9 with MMP8 and 30 [mu] M _{IC 50} of, an _{IC 50} of MMP3,1μM with an _{IC 50} of MMP1,150μM with an _{IC 50} of 1 [mu] M.

A further example of a more limited broad spectrum MMP inhibitor for use in the methods and devices disclosed herein is MMP9 inhibitor I (CTK8G1150), represented by the following structural formula:

MMP9 inhibitor I may inhibit the MMP13 having MMP9, and _{IC 50} of 113nM with an _{IC 50} of MMP1,5nM with an _{IC 50} of 1.05 nm.

An even more limited range of broad spectrum MMI inhibitors is MMI-166, represented by the structural formula:

MMI-166 is a third generation N-arylsulfonyl-α-amino acid hydroxymate-related MMP inhibitor that selectively inhibits the activity of MMP2, MMP9, and MMP14.

Cipemasat (Ro32-3555, Trocade) is another, more limited spectrum, broad spectrum N-arylsulfonyl-α-amino acid hydroxymate-related MMP inhibitor capable of inhibiting MMP1, MMP3, and MMP9, It is represented by the following structural formula.

MMI-270 is an even more limited range of broad-spectrum N-arylsulfonyl-α-aminocarboxylate zinc-bonded MMP inhibitors that can inhibit MMP2, MMP8, and MMP9 and have the following structural formula: expressed.

ABT-770 is yet another more limited range of N-arylsulfonyl-α-aminocarboxylate zinc-binding MMP inhibitors that inhibit gelatinases (eg, MMP2 and MMP9) and are represented by the following structural formula: To be done.

Purinomasat (AG-3340) is a more limited range of broad-spectrum N-arylsulfonyl-α-aminocarboxylate zinc-bound MMP inhibitors with specific selectivity for MMPs 2, 3, 9, 13, and 14. It is an agent and is represented by the following structural formula.

In another limitation, MMP inhibitors are a hydroxy-binding system that suppresses metabolism as well as MMP1. Examples of these MMP inhibitors are the tetrahydropyran MMP inhibitors, RS130830, and 239796-97-5.

Broad spectrum MMP inhibitors also include the family of tissue inhibitors of MMPs (TIMPs). As used herein, the term "TIMP" means an endogenous tissue inhibitor of metalloproteinases, which inhibits active matrix metalloproteinases, regulates pro-MMP activation, cell proliferation, and angiogenesis. It is known to be involved in physiological/biological functions including regulation. The human "TIMP family" contains four members, TIMP-1, TIMP-2, TIMP-3, and TIMP-4. The TIMP-1 protein is the most widely expressed and studied member of the TIMP family. Other members of the TIMP family include TIMP-2, TIMP-3, and TIMP-4. TIMP proteins not only share common structural features, including a series of conserved cysteine residues that form disulfide bonds essential for native protein structure (Brew et al., 2000), but also extensively overlap. It also has biological activity. The conserved N-terminal region of the TIMP protein is required for functional inhibitory activity, while the branched C-terminal region is thought to regulate the selectivity of inhibition and the binding efficiency of agents for MMPs (Maskos & Bode, 2003). .. However, apart from their ability to act as broad-spectrum MMP inhibitors, various TIMP family members also exert additional biological activities, including regulation of proliferation and apoptosis, in addition to regulation of angiogenic and inflammatory responses. Can be presented.

TIMP-1 has been found to inhibit most MMPs (except MMP-2 and MMP-14) and preferentially inhibit MMP-8. TIMP-1 is produced by a variety of cell types, secreted in soluble form, and widely distributed throughout the body. It is a widely glycosylated protein with a molecular weight of 28.5 kDa. TIMP-1 inhibits the active form of MMP and complexes with the proform of MMP9. Like MMP9, TIMP-1 expression is sensitive to many factors. Increased synthesis of TIMP-1 is caused by various reagents including TGF beta, EGF, PDGF, FGFb, PMA, all-trans retinoic acid (RA), IL1 and IL11.

TIMP-2 is a 21 kDa glycoprotein expressed by various cell types. It forms a non-covalent stoichiometric complex with both latent and activated MMPs. TIMP-2 shows a preference for inhibition of MMP-2.

TIMP-3 typically binds to ECM and inhibits the activity of MMP-1, MMP-2, MMP-3, MMP-9, and MMP-13. TIMP-3 exhibits 30% amino acid homology with TIMP-1 and 38% homology with TIMP-2. TIMP-3 has been shown to promote the shedding of transformed cells from the ECM and accelerate the morphological changes associated with cell transformation.

Due to its high affinity binding to ECM, TIMP-3 is unique among TIMPs. TIMP-3 has been shown to promote the shedding of transformed cells from the ECM and to promote the morphological changes associated with cell transformation. TIMP-3 contains a glucosaminoglycan (GAG) binding domain containing six amino acids (Lys30, Lys26, Lys22, Lys42, Arg20, Lys45), which are believed to be involved in cell surface association. To be TIMP-3 is the only TIMP that normally inhibits TACE (TNF-α-converting enzyme), which releases soluble TNF and is involved in IL-6 receptor processing and is central in the wound healing process. It is another metalloprotease that plays an essential role.

TIMP-4 inhibits all known MMPs and preferentially inhibits MMP-2 and MMP-7. TIMP4 exhibits 37% amino acid homology with TIMP1 and 51% homology with TIMP2 and TIMP3. TIMP4 is secreted extracellularly, primarily in heart and brain tissue, and appears to function in a tissue-specific manner with respect to extracellular matrix (ECM) homeostasis.

In some implementations, the broad spectrum MMP inhibitor provides for attachment of the MMP inhibitor to a surgical stapler or component thereof (such as the outer surface of a staple (eg, staple leg or staple crown)) or adjunct material. Materials that can enable or enhance can be included. The material may be an absorbent material (such as an absorbent polymer or absorbent lubricant), which may optionally be water soluble and/or ionically charged.

Suitable absorbable polymers capable of allowing or enhancing attachment of the broad spectrum MMP inhibitor to the outer surface may include synthetic and/or non-synthetic materials. Examples of non-synthetic materials include lyophilized polysaccharides, glycoproteins, bovine pericardium, collagen, gelatin, fibrin, fibrinogen, elastin, proteoglycans, keratin, albumin, hydroxyethyl cellulose, cellulose, oxidized cellulose, oxidized regenerated cellulose. regenerated cellulose (ORC), hydroxypropyl cellulose, carboxyethyl cellulose, carboxymethyl cellulose, chitin, chitosan, casein, alginic acid, and combinations thereof, but are not limited thereto. Examples of synthetic absorbent materials include, but are not limited to, poly(lactic acid) (PLA), poly(L-lactic acid) (PLLA), polycaprolactone, PCL), polyglycolic acid (PGA), poly(trimethylene carbonate, TMC), polyethylene terephthalate (PET), polyhydroxyalkanoate (PHA), glycolide and Copolymer with ε-caprolactone (PGCL), copolymer with glycolide and trimethylene carbonate, poly(glycerol sebacate), PGS, poly(dioxanone) , PDS), polyester, poly(orthoester), polyoxaester, polyetherester, polycarbonate, polyamide ester, polyanhydride, polysaccharide, poly(esteramide), tyrosine-based polyarylate, polyamine, tyrosine-based polyimino. Carbonate, tyrosine-based polycarbonate, poly(D,L-lactide-urethane), poly(hydroxybutyrate), poly(B-hydroxybutyrate), poly(ε-caprolactone), polyethylene glycol (polyethyleneglycol, PEG), poly[ Bis(carboxylate phenoxy)phosphazene] poly(amino acid), pseudopoly(amino acid), absorbent polyurethane, poly(phosphazine), polyphosphazene, polyalkylene oxide, polyacrylamide, polyhydroxyethyl methyl acrylate, polyvinylpyrrolidone, polyvinyl alcohol, Poly(caprolactone), polyacrylic acid, polyacetate, polypropylene, aliphatic polyester, glycerol, copoly(ether-ester), polyalkylene oxalate, polyamide, poly(iminocarbonate), polyalkylene oxalate, and combinations thereof Can be mentioned. In various embodiments, the polyester can be selected from the group consisting of polylactide, polyglycolide, trimethylene carbonate, polydioxanone, polycaprolactone, polybutester, and combinations thereof.

In some embodiments, the broad spectrum MMP inhibitor can be absorbed or encapsulated in synthetic or non-synthetic absorbable polymers. In addition, the polymer can have one or more inducing aspects associated with it to facilitate the attachment of the broad spectrum MMP inhibitor to the area of the polymer-coated staple. For example, the absorbent polymer can be porous to allow the liquid containing the broad spectrum MMP inhibitor to pool and collect in the pores that are retained when the liquid dries. Additionally, one or both of the broad spectrum MMP inhibitor or the absorbing polymer can be compounded with an ionic charge, thereby electrostatically attracting them. Absorbent polymers (eg, polyurethanes) can also be formulated so that the broad spectrum MMP inhibitor is covalently attached to the polymer chain itself as a pendant element. Finally, the water solubility of the polymer itself can be manipulated to allow the polymer and the broad spectrum MMP inhibitor to mix before the water is removed from the structure leaving behind the drug and polymer blend.

In at least some implementations, the absorbable lubricant is a broad spectrum MMP inhibitor to a surgical stapler or component thereof (such as the outer surface of a staple (eg, staple leg or staple crown)) or adjunct material. It can be used to allow or enhance adhesion. Suitable absorbable lubricants include, for example, without limitation, magnesium stearate, sodium stearate, calcium stearate, powdered stearic acid, talc, paraffin, cocoa butter, graphite, lycopodium, or combinations thereof, and the like. Any conventional tablet water-insoluble lubricant can be included. Absorbent lubricants can be derived from stearates, such as magnesium stearate, sodium stearate, calcium stearate, and fatty acids such as stearic acid.

Implantable Supplements A variety of implantable supplements are provided for use with surgical stapling instruments. “Auxiliary material” is also referred to herein as “auxiliary material”. The auxiliary material can have various configurations and can be formed from various materials. Generally, the adjunct material may be formed from one or more of films, foams, injection molded thermoplastics, vacuum thermoformed materials, fibrous structures, and hybrids thereof. Adjuvants may also include one or more bio-derived materials and one or more drugs. Each of these materials is discussed in more detail below.

The adjunct may be formed from foam, such as closed cell foam, open cell foam, or sponge. An example of how such adjuncts can be produced is from animal-derived collagen, such as porcine tendon, which can then be processed and lyophilized to obtain a foamed structure. Examples of various foaming aids are further described in the above-referenced US Pat. No. 8,393,514, entitled "Selectively Orientable Implantable Fastener Cartridge", filed September 30, 2010. There is.

Also, the adjunct may be formed from a film formed from any suitable material discussed below or combinations thereof. The film can include one or more layers, each of which can have a different degradation rate. Further, the film may releasably retain various regions formed therein, eg, one or more agents in many different forms (eg, at least one broad spectrum MMP inhibitor). Can have a reservoir that can. The reservoir with at least one drug disposed therein can be sealed using one or more different coating layers, which can include absorbable or non-absorbable polymers. The film can be formed in various ways. For example, the film can be an extruded film or a compression molded film.

Also, the adjunct may be formed from injection molded thermoplastic or vacuum thermoformed materials. Examples of various molding aids are further filed in U.S. Patent Application Publication No. 2013/0221065 (filed under the title "Fastener Cartridge Comprising A Releasably Attached Tissue Thickness Compensator", February 8, 2013). .. This document is incorporated herein by reference in its entirety. The auxiliary material can also be a fiber-based grating. The lattice can be woven, knitted, or non-woven such as meltblown, needlepunched, or heat-constructed loose woven. The adjunct may have multiple regions, which may be formed from the same type of lattice or different types of lattice, which together may form the adjunct in many different ways. For example, the fibers can be woven, braided, braided, or otherwise tied together to form a regular or irregular structure. The fibers can be tied together so that the resulting auxiliaries are relatively loose. Alternatively, the adjunct may include fibers that are closely interconnected. The adjuncts may be in the form of sheets, tubes, helices, or any other structure that may include soft and/or stiffer reinforcements. The adjunct may be configured such that certain regions may have denser fibers while other regions have less dense fibers. The fiber density can vary in different directions along one or more dimensions of the adjunct, based on the intended use of the adjunct.

The adjunct material can also be a hybrid structure such as a laminated composite or melt-lock interconnected fiber. Examples of various hybrid structural auxiliaries are U.S. Patent Application Publication No. 2013/0146643 (Title of Invention "Adhesive Film Laminate", filed February 8, 2013) and U.S. Patent No. 7,601,118 ( The title of the invention is further described in “Minimally Invasive Medical Implant And Insertion Device And Method For Using The Same”, filed September 12, 2007). These documents are incorporated herein by reference in their entirety.

The auxiliary material can be formed from a variety of materials. The material may be used in various embodiments for different purposes. The material can be selected according to the desired treatment to be provided to the tissue to promote tissue ingrowth. The materials described below can be used to form the adjunct in any desired combination.

The material can include bioabsorbable and biocompatible polymers, including homopolymers and copolymers. Non-limiting examples of homopolymers and copolymers include p-dioxanone (PDO or PDS), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), trimethylene carbonate (TMC). ), and polylactic acid (PLA), poly(glycolic acid-co-lactic acid) (PLA/PGA) (for example, PLA/PGA materials used in Vicryl, Vicryl Rapid, PolySorb, and Biofix), polyurethane (Elastane, Biospan). , Tecoflex, Bionate, and Pellethane fibers), polyorthoesters, polyanhydrides (eg, Gliadel and Biodel polymers), polyoxaesters, polyesteramides, and tyrosine-based polyesteramides. The copolymers are also poly(lactic-co-polycaprolactone) (PLA/PCL), poly(L-lactic-co-polycaprolactone) (PLLA/PCL), poly(glycolic acid-co-trimethylene carbonate) (PGA/ TMC) (eg Maxon), poly(glycolic acid-co-caprolactone) (PCL/PGA) (eg Monocryl and Capgly), PDS/PGA/TMC (eg Biosyn), PDS/PLA, PGA/PCL/TMC. /PLA (eg Caprosyn), and LPLA/DLPLA (eg Optima) may also be included.

The adjuncts described herein may releasably retain at least one drug therein. The drug may be selected from a number of different drugs. Agents include, but are not limited to, any of the broad spectrum MMP inhibitors disclosed herein.

Other agents for use with adjuncts include, but are not limited to, antibacterial agents such as antibacterial agents and antibiotics, antifungal agents, antiviral agents, anti-inflammatory agents, growth factors, analgesics, It includes anesthetics, tissue matrix degeneration inhibitors, anti-cancer agents, hemostatic agents, as well as other agents that elicit a biological response.

Adjuvants may also include other active cell cultures (eg, autologous tissue in dice, agents used in stem cell therapy (eg, Biosutures and Cellerix SL), hemostatics, and tissue healing agents, such as tissue healing agents. Non-limiting examples of hemostatic agents include non-limiting examples of hemostatic agents, such as oxidized regenerated cellulose (ORC) (eg Surgicel and Interceed), fibrin/thrombin (eg Thrombin-JMI, TachoSil, Tiseel, Froseal, Evicel, TachoComb). , Vivostat, and Everest), autologous platelet plasma, gelatin (eg Gelfilm and Gelfoam), microfibers (eg yarns and textiles) or other structures based on hyaluronic acid, or hyaluronic acid-based hydrogels. Hemostatic agents may also include polymeric sealants such as bovine serum albumin and glutaraldehyde, human serum albumin and polyethylene cross-linking agents, and ethylene glycol and trimethylene carbonate, etc. Polymer sealants include Focal. Mention may be made of the FocalSeal surgical sealant developed by Inc.

Non-limiting examples of antibacterial agents include silver ions, aminoglycosides, streptomycin, polypeptides, bacitracin, triclosan, tetracycline, doxycycline, minocycline, demeclocycline, tetracycline, oxytetracycline, chloramphenicol, nitrofuran, furazolidone, Nitrofurantoin, beta-lactam, penicillin, amoxicillin, amoxicillin +, clavulanic acid, azlocillin, flucloxacillin, ticarcillin, piperacillin + tazobactam, tazosin, Biopiper TZ, zocine, carbapenem, imipenem, melenem, nepenemem, melopenem, nepenemem, melopenem , Panipenem/betamipron, quinolone, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, sulfonamide, mafenide, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadiazine, sulfadiazine, sulfadiazine, sulfadiazine , Sulfamethizole, sulfamethoxazole, sulfasalazine, sulfisoxazole, bactrim, protosyl, ansamycin, geldanamycin, herbimycin, fidaxomycin, glycopeptide, teicoplanin, vancomycin, telavancin, dalbabacin, oritavancin , Lincosamide, clindamycin, lincomycin, lipopeptide, daptomycin, macrolide, azithromycin, clarithromycin, erythromycin, roxithromycin, terithromycin, spiramycin, oxazolidinone, linezolid, aminoglycoside, amikacin, gentamicin, Includes kanamycin, neomycin, netilmycin, tobramycin, paromycin, paromomycin, cephalosporins, ceftobiprole, ceftrozan, cefcridine, flomoxef, monobactam, aztreonam, colistin, and polymyxin B.

Non-limiting examples of antifungal agents are triclosan, polyene, amphotericin B, candicidin, Philippines, hamycin, natamycin, nystatin, rimocidin, azole, imidazole, triazole, thiazole, allylamine, amorolfine, butenafine, naphthifine, terbinafine, echinocandin, anidura. Includes fanzine, caspofungin, micafungin, ciclopirox, and benzoic acid.

Non-limiting examples of antiviral agents include shelling inhibitors such as amantadine, rimantadine, pleconaril and the like; reverse transcription inhibitors such as acyclovir, lamivudine, antisense, fomivirsen, morpholino, ribozymes, rifampicin; and antiviral agents. For example, it includes cyanovirin-N, griffithsin, cytovirin, α-lauryl-L-arginine ethyl ester (LAE), and silver ion.

Non-limiting examples of anti-inflammatory agents include non-steroidal anti-inflammatory drugs (eg salicylate, aspirin, diflunisal, propionic acid derivatives, ibuprofen, naproxen, fenoprofen, and loxoprofen), acetic acid derivatives (eg tolmetin, sulindac, And diclofenac), enolic acid derivatives (eg, piroxicam, meloxicam, droxicam, and lornoxicam), anthranilic acid derivatives (eg, mefenamic acid, meclofenamic acid, and flufenamic acid), selective COX-2 inhibitors (eg, celecoxib (celeb). Rex), parecoxib, rofecoxib (Vioxx), sulfoneanilide, nimesulide, and clonixin), immunoselective anti-inflammatory derivatives, corticosteroids (eg, dexamethasone), and iNOS inhibitors.

Non-limiting examples of growth factors include factors that are cell signaling molecules that stimulate cell growth, healing, remodeling, proliferation, and differentiation. Exemplary growth factors can be short-range (paracrine), long-range (endocrine), or self-stimulating (autocrine). Further examples of growth factors are growth hormones (eg, recombinant growth factors, neutropins, humantropes, genotropins, norditropins, seizens, omnitropes, and biosynthetic growth factors), epidermal growth factors (EGF) (eg, Inhibitors, gefitinib, erlotinib, afatinib, and cetuximab), heparin-binding EGF-like growth factors (eg epiregulin, betacellulin, amphiregulin, and epigen), transforming growth factor alpha (TGF-a), neuroregulin 1 -4, fibroblast growth factor (FGF) (for example, FGF-1-2, FGF2, FGF11-14, FGF18, FGF15/19, FGF21, FGF23, FGF7, or keratinocyte growth factor (KGF), FGF10, or KGF2). , And phenytoin), insulin-like growth factor (IGF) (eg, IGF-1, IGF-2, and platelet-derived growth factor (PDGF)), vascular endothelial growth factor (VEGF) (eg, inhibitor, bevacizumab, ranibizumab, VEGF-A, VEGF-B, VEGF-C, VEGF-D, and becaplermin).

Further non-limiting examples of growth factors are prepared using granulocyte-macrophage colony stimulating factor (GM-CSF) (eg inhibitors that inhibit the inflammatory response, and recombinant DNA technology and by recombinant yeast-derived sources. GM-CSF), granulocyte colony stimulating factor (G-CSF) (eg, filgrastim, renograstim, and neupogen), tissue growth factor beta (TGF-B), leptin, and interleukin ( IL) (eg, IL-1a, IL-1b, canakinumab, IL-2, aldesleukin, interking, denileukin diftitox, IL-3, IL-6, IL-8, IL-10, IL-11, and Oprelvekin) is included. Non-limiting examples of growth factors further include erythropoietin (eg, darbepoetin, epocept, dynepo, epomax, neorecormon, silapo, and retacrit).

Non-limiting examples of analgesics include anesthetics, opioids, morphine, codeine, oxycodone, hydrocodone, buprenorphine, tramadol, non-anesthetics, paracetamol, acetaminophen, NSAIDs, and flupirtine.

Non-limiting examples of anesthetics include local anesthetics (eg, lidocaine, benzocaine, and ropivacaine) and general anesthetics.

Non-limiting examples of anti-cancer agents include monoclonal antibodies, bevacizumab (Avastin), cell/chemo-chemotactic agents, alkylating agents (eg bifunctional, cyclophosphamide, mechlorethamine, chlorambucil, melphalan, monofunctional, Nitrosoureas and temozolomides), anthracyclines (eg daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, and valrubicin), cytoskeletal degradants (eg paclitaxel and docetaxel), cell division by inhibiting microtubule function. Restricting epothilone agents, inhibitors that block various enzymes required for cell division or specific cell functions, histone deacetylase inhibitors (eg, vorinosutato and romidepsin), topoisomerase I inhibitors (eg, irinotecan and Topotecan), topoisomerase II inhibitors (eg, etoposide, teniposide, and tafluposide), kinase inhibitors (eg, bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, and bismodedib), nucleotide analogues (eg, azacitidine, azathioprine, capecitabine, capecitabine, capecitabine, capecitabine Cytarabine, Doxyfluridine, Fluorouracil, 5-FU, Adolsyl, Carrack, Effix, Efdex, Fluoroplex, Gemcitabine, Hydroxyurea, Mercaptopurine, and Thioguanine), cleave DNA, interrupt DNA rewinding/winding Peptide antibiotics (eg bleomycin and actinomycin), platinum anti-neoplastic agents that crosslink DNA and inhibit DNA repair and/or synthesis (eg carboplatin, cisplatin, oxaliplatin, and eloxatin), retinoids (eg , Tretinoin, altretinoin, and bexarotene), vinca alkaloids that inhibit mitosis and microtubule formation (eg, vinblastine, vincristine, vindesine, vinorelbine), anti-ileus agents, prokinetic agents, immunosuppressants (eg, tacrolimus). ), blood aspect modifiers (eg, vasodilators, viagra, and nifedipine), 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA) reductase inhibitors (eg, atorvastatin), and anti-angiogenic agents. Including.

Exemplary agents also include agents that passively contribute to wound healing, such as nutrition, oxygen scavengers, amino acids, collagen synthesizers, glutamine, insulin, butyrate, and dextran. Exemplary agents also include anti-adhesion agents. Non-limiting examples also include hyaluronic acid/carboxymethyl cellulose (seprafilm), oxidized regenerated cellulose (Interceed), and icodextrin 4% (Extraneal, Adept).

Adjuvants based on the described techniques can be associated with at least one agent (eg, an MMP inhibitor) in many different ways to provide a desired effect in a desired manner, such as on tissue ingrowth. can do. The at least one agent may be configured to be released from the adjunct in a plurality of spatial and temporal patterns to trigger the desired healing process at the treatment site. The drug may be disposed within the adjunct, bonded to the adjunct, incorporated within the adjunct, dispersed within the adjunct, or otherwise associated with the adjunct. For example, the adjunct may have one or more regions releasably retaining one or more different drugs therein. These regions can be separate reservoirs of different sizes and shapes that hold the drug therein in different ways and in different ways, or other separate or continuous regions within the adjunct. In some aspects, the particular configuration of the adjunct may allow one drug or two or more different drugs to be releasably retained therein.

Regardless of how the drug is placed in the adjunct, an effective amount of the at least one drug is in a pellet, which can be in the form of a container, such as a microcapsule, a microbead, or any other container. Can be encapsulated. The container can be formed from a bioabsorbable polymer.

Targeted delivery and release of at least one drug from the adjunct can be accomplished in a number of ways depending on various factors. Generally, the at least one drug can be released from the adjunct material as a bolus dose such that the drug is released substantially immediately after the adjunct material is delivered to the tissue. Alternatively, at least one drug may be released from the adjunct material over a specified period of time, which may be minutes, hours, days, or longer. The rate of timed release and the amount of drug released depends on a variety of factors, including the rate of degradation of the area where the drug is released, the one used to hold the drug in the adjunct. Alternatively, it may depend on the degradation rate of two or more coatings or other structures, the environmental conditions of the treatment site, and various other factors. In some aspects, when the adjunct has more than one drug disposed therein, the bolus dose release of the first drug begins to release after the first drug is released. The release of the two drugs may be controlled. The adjunct may include multiple agents. The agents may each affect the release of one or more other agents in any suitable manner.

Release of the at least one drug as a bolus dose or as a timed release may occur or begin substantially immediately after the adjunct material is delivered to the tissue, or for a predetermined period of time. May be delayed until. The delay may depend on the structure and nature of the adjunct or one or more of its areas.

Temporary Inhibition of Wound Healing In a further aspect, provided herein is a method for temporarily inhibiting wound healing at a surgical site immediately following surgical stapling of tissue with a surgical stapler. The method attaches an adjunct material to an end effector of a surgical stapler and engages tissue between the cartridge assembly and the anvil of the end effector,
Actuating the end effector to eject staples from the cartridge assembly into the tissue. The staples may extend through the supplemental material to maintain it at the surgical site. At least one of the plurality of staple portions (eg, staple legs and/or crowns) and/or adjunct material comprises a releasably effective amount of at least one broad spectrum MMP inhibitor. The term "effective amount" as used herein with respect to the broad spectrum MMP inhibitors released in accordance with the devices and methods herein means an increase in strength within the tissue 1 to 3 days immediately following tissue stapling. Means an amount of a broad spectrum MMP inhibitor sufficient to inhibit at least two MMPs to the extent that Release of the broad spectrum MMP inhibitor at the stapling site in the tissue prevents MMP-mediated extracellular matrix degeneration during wound healing in the tissue in a predetermined manner.

In some implementations, the broad spectrum MMP inhibitor is configured to be released from the staple and/or adjunct material into the surrounding tissue for 2-3 days after staple insertion. For example, a broad spectrum MMP inhibitor begins to degrade about 48 hours after staple insertion into tissue and begins to release its contents, followed by 24-36 hours (about 1, 2, 3, 4, 5, 6). , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, , 32, 33, 34, 35, or 36 hours), followed by encapsulation in an absorbent polymer (such as any of the absorbent polymers disclosed herein).

A sufficient amount of the broad spectrum MMP inhibitor is released from the plurality of staples and/or adjunct materials to produce one or more MMP inhibitors (tissue stapling expressed at the stapling site immediately after staple insertion. Inhibits at least 5% of the proteolytic activity of MMP inhibitors such as MMP inhibitors expressed within 1-3 days after (eg 5%, 10%, 15%, 20 of proteolytic activity) %, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 85%, 85%, 90%, 95%, or 100% Of either). In some embodiments, a sufficient amount of a broad spectrum MMP inhibitor is released from the plurality of staples and/or adjunct materials after staple insertion into the tissue to provide about 0.1 nM, 0 within the wound site. .2nM, 0.3nM, 0.4nM, 0.5nM, 0.6nM, 0.7nM, 0.8nM, 0.9nM, 1nM, 2nM, 3nM, 4nM, 5nM, 6nM, 7nM, 8v, 9nM, 10nM , 11nM, 12nM, 13nM, 14nM, 15nM, 1nM 6nM, 17nM, 18nM, 19nM, 20nM, 21nM, 22nM, 23nM, 24nM, 25nM, 30nM, 35nM, 40nM, 45nM, 50nM, 55nM, 60nM, 65nM, 65nM, 65nM, 65nM, 65nM, 65nM, 65nM, and 65nM 75 nM, 80 nM, 85 nM, 90 nM, 95 nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1 μM, 2 μM, 3 μM, 4 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 35 μM, 40 μM, 45 μM, 50 μM, 55 μM, 60 μM, 65 μM, 70 μM, 75 μM, 80 μM, 85 μM, 90 μM, 95 μM, 100 μM, 125 μM, 150 μM, 175 μM, 200 μM, 225 μM, 250 μM, 275 μM, 300 μM, 325 μM, 350 μM, 375 μM, 375 μM, 375 μM, 375 μM Broad spectrum of at least about 0.1 nM to about 500 μM at the wound site surrounding the staple, such as any of 425 μM, 450 μM, 475 μM, or 500 μM or more of a broad spectrum MMP inhibitor, including numbers falling between these values. Ensure the concentration of spectral MMP inhibitor.

In a further implementation, release of the broad spectrum MMP inhibitor from multiple staples and/or adjuncts after staple insertion into tissue results in increased production and maintenance of collagen fibers in the ECM that directly surrounds the staple insertion site. Due to this, it increases the strength of the tissue at the wound site. In some embodiments, the staples releasably coated with at least one broad spectrum MMP inhibitor and/or the tissue surrounding the adjunct material are staples not releasably coated with at least one broad spectrum MMP inhibitor. And/or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% compared to the tissue surrounding the auxiliary material. , 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% or more of increased collagen.

Those skilled in the art will recognize that the present invention has application in conventional minimally invasive and open surgical instruments, as well as in robotic assisted surgery.

The devices disclosed herein can be designed to be disposed of after a single use, or can be designed to be used multiple times. However, in either case, the device can be reconditioned for reuse after at least one use. Reconditioning can include any combination of a disassembly process of the device, a subsequent cleaning or replacement of specific parts, and a subsequent reassembly process. In particular, the device can be disassembled and any number of the particular pieces or parts of the device can be selectively replaced or removed in any combination. After cleaning and/or replacement of certain parts, the device can be reassembled for later use, either at a reconditioning facility or by a surgical team immediately prior to a surgical procedure. Those of ordinary skill in the art will appreciate that reconditioning of a device can utilize a variety of techniques for disassembly, cleaning/replacement, and reassembly. Use of such techniques, and the resulting reconditioned device, are all within the scope of the present application.

Additional exemplary structures and components are described in US patent application Ser. No. 15/621,551, entitled “Surgical Stapler,” filed on the same date herewith and incorporated herein by reference in its entirety. with End Effector Coating", No. 15/621,565 ("Surgical Fastener Device For The Prevention of ECM DEGRADUAL ACTION"), and No. 15/621,572 (Surgical Surgical). Healing").

Those skilled in the art will appreciate further features and advantages of the invention based on the above-described embodiments. Accordingly, the invention is not to be limited by what has been particularly shown and described, except as indicated by the appended claims. All publications and references cited in this specification are expressly incorporated herein by reference in their entirety.

Embodiments
(1) A staple cartridge assembly for use with a surgical stapler, comprising:
A cartridge body having a plurality of staple cavities, each staple cavity having one of a plurality of surgical staples disposed within the staple cavity.
An effective amount of at least one broad spectrum matrix metalloproteinase (MMP) inhibitor effective to prevent MMP-mediated extracellular matrix degeneration during wound healing in tissue in a predetermined manner. assembly.
(2) The assembly of embodiment 1, wherein the at least one broad spectrum MMP inhibitor is disposed on at least a portion of the plurality of staples.
(3) The assembly according to embodiment 1, wherein the MMP inhibitor inhibits at least five of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP12, MMP13, MMP14, and MMP16.
(4) The assembly according to embodiment 3, wherein the MMP inhibitor comprises an anti-inflammatory agent.
(5) The assembly according to embodiment 4, wherein the MMP inhibitor is GM6001 (ilomastat).

(6) The assembly according to embodiment 3, wherein the MMP inhibitor is a tetracycline class antibiotic.
(7) The assembly according to embodiment 6, wherein the tetracycline class antibiotic is doxycycline or minocycline.
(8) The MMP inhibitor is selected from the group consisting of Levimasat, Batimastat (BB-94), BB-1101, CGS-27023-A, Marimasat, ONO-4817, Ro28-2653, and SB-3CT. The assembly of embodiment 3, wherein the assembly is one or more inhibitors.
(9) The assembly according to embodiment 1, wherein the MMP inhibitor inhibits 4 or less of MMP1, MMP2, MMP3, MMP9, MMP9, MMP12, MMP13, MMP14, and MMP16.
(10) 1 wherein the MMP inhibitor is selected from the group consisting of MMI-166, Tanomasterat, Cipemasterat, MMI-270, ABT-770, Purinomasterat, Tetrahydropyran, RS-130830, and 239796-97-5. The assembly of embodiment 9, which is one or more inhibitors.

(11) further comprising a biocompatible adjunct material releasably retained on the cartridge body and configured to be delivered to tissue by deployment of the staples within the cartridge body, wherein the MMP inhibitor is The assembly of embodiment 1, wherein the assembly is encapsulated on the adjunct material by an absorbable polymer or attached as a pendant molecule on the biocompatible adjunct material.
(12) A method for temporarily inhibiting wound healing at a surgical site immediately after surgical stapling of tissue with a surgical stapler, comprising:
Engaging tissue between the cartridge assembly and the end effector anvil;
Actuating the end effector to eject staples from the cartridge assembly into the tissue,
At least one of the portions of the plurality of staples comprises an effective amount of at least one broad spectrum matrix metalloproteinase (MMP) inhibitor, the release of the MMP inhibitor causing wounds in the tissue in a predetermined manner. A method of preventing MMP-mediated extracellular matrix degeneration during healing.
(13) The method according to embodiment 12, wherein the MMP inhibitor inhibits at least five of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP12, MMP13, MMP14, and MMP16.
(14) The MMP inhibitor is levimaster, batimastat (BB-94), doxycycline, minocycline, GM6001 (ilomastat), and BB-1101, CGS-27023-A, marimastat, ONO-4817, Ro28-2653, and SB. The method according to embodiment 13, which is one or more inhibitors selected from the group consisting of -3CT.
(15) The method according to embodiment 12, wherein the MMP inhibitor is released immediately after delivery to the tissue.

(16) The embodiment according to embodiment 12, wherein the MMP inhibitor inhibits four or less that inhibits at least five of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP12, MMP13, MMP14, and MMP16. the method of.
(17) The MMP inhibitor is 1 selected from the group consisting of MMI-166, tanomasterat, cipemasterat, MMI-270, ABT-770, purinomasterat, tetrahydropyran, RS-130830, and 239796-97-5. 17. The method of embodiment 16, which is one or more inhibitors.
(18) The assembly further comprises a biocompatible adjunct material releasably retained on the cartridge body and configured to be delivered to tissue by deployment of the staples within the cartridge body; 14. The method of embodiment 13, wherein the MMP inhibitor is encapsulated on the adjunct material by an absorbable polymer or attached as a pendant molecule on the biocompatible adjunct material.
(19) The method according to embodiment 18, wherein the MMP inhibitor is released from the auxiliary material 1 to 3 days after delivery to the tissue.
(20) The method according to embodiment 13, wherein the tissue is colon tissue.

Claims (11)

A staple cartridge assembly for use with a surgical stapler, comprising:
A cartridge body having a plurality of staple cavities, each staple cavity having one of a plurality of surgical staples disposed within the staple cavity.
An effective amount of at least one broad spectrum matrix metalloproteinase (MMP) inhibitor effective to prevent MMP-mediated extracellular matrix degeneration during wound healing in tissue in a predetermined manner. assembly. The assembly of claim 1, wherein the at least one broad spectrum MMP inhibitor is disposed on at least a portion of the plurality of staples. The assembly according to claim 1, wherein the MMP inhibitor inhibits at least five of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP12, MMP13, MMP14, and MMP16. The assembly of claim 3, wherein the MMP inhibitor comprises an anti-inflammatory agent. The assembly of claim 4, wherein the MMP inhibitor is GM6001 (Ilomasat). 4. The assembly of claim 3, wherein the MMP inhibitor is a tetracycline class antibiotic. 7. The assembly of claim 6, wherein the tetracycline class antibiotic is doxycycline or minocycline. The MMP inhibitor is one selected from the group consisting of Levimasat, Batimastat (BB-94), BB-1101, CGS-27023-A, Marimasat, ONO-4817, Ro28-2653, and SB-3CT, or The assembly of claim 3, wherein there are two or more inhibitors. The assembly of claim 1, wherein the MMP inhibitor inhibits 4 or less of MMP1, MMP2, MMP3, MMP9, MMP9, MMP12, MMP13, MMP14, and MMP16. The MMP inhibitor is one or two selected from the group consisting of MMI-166, tanomastat, cipemaster, MMI-270, ABT-770, purinomaster, tetrahydropyran, RS-130830, and 239796-97-5. 10. The assembly of claim 9, which is one or more inhibitors. Further comprising a biocompatible adjunct material releasably retained on the cartridge body and configured to be delivered to tissue by deployment of the staples within the cartridge body, wherein the MMP inhibitor is absorbable. The assembly of claim 1 encapsulated by a polymer on the adjunct material or attached as a pendant molecule on the biocompatible adjunct material.

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